Transplantation of human islet cells can provide good glycemic control in diabetic recipients without exogenous insulin. However, a major factor limiting its application is the recipient's need to adhere to life-long immunosuppression, which has serious side effects. Microencapsulating the human islets is a strategy that should prevent rejection of the grafted tissue without the need for anti-rejection drugs.
However, despite promising studies in various animal models, the encapsulated human islets so far have not made an impact in the clinical setting. Many non-immunological and immunological factors such as biocompatibility, reduced immunoprotection, hypoxia, pericapsular fibrotic overgrowth, effects of the encapsulation process, and post-transplant inflammation hamper the successful application of this promising technology (Vaithilingam V, et al. Diabet Stud, 8(1):51-67 (2011)).
One major challenge to clinical application of encapsulated cells and other biomaterials and medical devices is their potential to induce a non-specific host response (Williams D F. Biomaterials 29(20):2941-53 (2008); Park H, et al. Pharm Res 13(12):1770-6 (1996); Kvist P H, et al. Diabetes Technol 8(4):463-75 (2006); Wisniewski N, et al. J Anal Chem 366(6):611-21 (2000); Van der Giessen W J, et al. Circulation 94(7):1690-7 (1996); Granchi D, et al. J Biomed Mater Res 29(2):197-202 (1995); Ward C R, et al. Obstet Gynecol 86(5):848-50 (1995); Remes A, et al. Biomaterials 13(11):731-43 (1992)). This reaction involves the recruitment of early innate immune cells such as neutrophils and macrophages, followed by fibroblasts which deposit collagen to form a fibrous capsule surrounding the implanted object (Williams D F. Biomaterials 29(20):2941-53 (2008); Remes A, et al. Biomaterials 13(11):731-43 (1992); Anderson J M, et al. Semin Immunol 20(2):86-100 (2008); Anderson J M, et al. Adv Drug Deliver Rev 28(1):5-24 (1997); Abbas A K, et al. Pathologic Basis of Disease. 7th ed. Philadelphia: W.B Saunders (2009)). Fibrotic cell layers can hinder electrical (Singarayar S, et al. PACE 28(4):311-5 (2005)) or chemical communications and prevent transport of analytes (Sharkawy A A, et al. J Biomed Mater Res 37(3):401-12 (1997); Sharkawy A A, et al. J Biomed Mater Res 40(4):598-605 (1998); Sharkawy A A, et al. J Biomed Mater Res 40(4):586-97 (1998)) and nutrients, thus leading to the eventual failure of many implantable medical devices such as immunoisolated pancreatic islets (De Groot M, et al. J Surg Res 121(1):141-50 (2004); De Vos P, et al. Diabetologia 40(3):262-70 (1997); Van Schilfgaarde R, et al. J Mol Med 77(1):199-205 (1999)).
The incorporation of controlled-release delivery systems of anti-inflammatory drugs into medical devices has been proposed to mitigate host response and improve device durability (Wu P, et al. Biomaterials 27(11):2450-67 (2006); Dash A K, et al. J Pharmacol Toxicol 40(1):1-12 (1998); Labhasetwar V, et al. J Appl Biomater 2(3):211-2 (1991); Morais J M, et al. AAPS J 12(2):188-96 (2010); Hunt J A, et al. J Mater Sci: Mater Med 3(3):160-9 (1992)). This approach has shown promise in a number of clinical applications. For example, controlled elution of steroids from pace-maker leads reduces fibrosis formation and enhances long-term electrical communication between the leads and surrounding cardiac tissue (Singarayar S, et al. PACE 28(4):311-5 (2005)). However, similar attempts to improve the performance of other medical devices such as immunoisolated islets for diabetes therapy have proven challenging (Williams D F. Biomaterials 29(20):2941-53 (2008)).
Researchers developing controlled-release drug formulations to mitigate host response have largely focused on decreasing the number of inflammatory cells infiltrating the host-device interface. However, various factors in the design of controlled-release formulations such as drug selection, drug loading, particle sizes and corresponding release kinetics can dynamically affect a range of biological activities in the host response. The presence of anti-inflammatory drugs may alter not only the quantity and variety of immune cells recruited but also the kinetics of cellular activities such as the secretion of inflammatory enzymes or cell signaling pathways (Vane J R, et al. Inflamm Res 47(14):78-87 (1998); Rhen T, et al. New Engl J Med 353(16):1711-23 (2005)). In vivo cellular secretory products might affect the degradation rate of the polymeric matrix (Erfle D J, et al. Cardiovasc Pathol 6(6):333-40 (1997); Labow R S, et al. Biomaterials 16(1):51-9 (1995); Labow R S, et al. Biomaterials 23(19):3969-75 (2002)) used to encapsulate drugs, and are partly responsible for the discrepancy between in vitro and in vivo release kinetics (Zolnik B S, et al. J Control Release 127(2):137-45 (2008)).
There remains a substantial need to better understand the immunomodulatory effects of anti-inflammatory drugs on the host-tissue biology at the implant site (Wu P, et al. Biomaterials 27(11):2450-67 (2006)). Such knowledge can lead to better design of controlled-release drug delivery systems to improve the biocompatibility of implanted medical devices.
It is an object of the present invention to provide a cell encapsulation system for transplanting cells with reduced pericapsular fibrotic overgrowth.
It is a further object of the invention to provide a cell encapsulation system for transplanting cells that inhibits a cellular immune response.
It is a further object of the invention to provide a method for identifying anti-inflammatory drugs formulations that inhibit inflammation caused by encapsulated cells.
It is a further object of the invention to provide improved methods for treating diabetes using encapsulated islet cells.